Neutral red retention (NRR) assay was used to evaluate the effects of sexual maturation, spawning, and post spawning recovery on lysosomal membrane integrity in hemocytes of two size classes of Pacific oysters. Large (102.23 ± 1.79 mm in height and 24 mo old) and small (52.47 ± 2.08 mm in height and 14 mo old) oysters were divided respectively into two groups: Group H was fed a high quantity of microalgae (approximately 2 × 106 cells mL−1 at a rate of 1.0 L per oyster per day) to enhance gonad development, whereas Group L was fed a low quantity of microalgae (same cell concentrations but at a rate of 0.15 L per oyster per day) to minimize changes in their dry meat weight and NRR time. The results showed that prior to spawning the decrease in lysosomal membrane stability in Group H were negatively correlated with the changes in dry meat weight. After spawning, the dry meat weight reduced to a level that was not significantly different from their initial values on day 0. This indicates that prior to spawning the increase in dry meat weight mainly resulted from the growth of gonad tissue, and thus the stress experienced by the oysters during this period was mainly related to gametogenesis or its related metabolism and/or biological functions. The results also showed that spawning further impaired lysosomal membrane stability (P < 0.05). After spawning the NRR times remained at the lowest recorded levels for a period before recovering to levels corresponding with the water temperature in which the animals were maintained. The smaller oysters recovered from the stress of spawning much faster than the larger animals (P < 0.05). Prior to spawning the dry meat weights of large and small oysters increased by approximately 85% in the first 42 days, whereas during the same period after spawning they only increased slightly, suggesting that the available energy was mainly used to recover from the stress created by spawning.